AMIODARONE IS A DOSE-DEPENDENT NONCOMPETITIVE AND COMPETITIVE INHIBITOR OF T3 BINDING TO THYROID-HORMONE RECEPTOR SUBTYPE BETA-1, WHEREAS DISOPYRAMIDE, LIGNOCAINE, PROPAFENONE, METOPROLOL, DL-SOTALOL, AND VERAPAMIL HAVE NO INHIBITORY EFFECT

The cardiovascular and electrophysiological effects of amiodarone resemble those of hypothyroidism. The drug has a structural resemblance to thyroid hormone (T3). Previous studies indicate that amiodarone exerts its major effect through antagonism of T3, probably as a result of inhibition of ligand binding to the thyroid hormone receptor (ThR). There are five subtypes of ThR, of which the beta(1) is the most prominent in the human heart. Our first aim was to investigate whether ThR is involved in a general antiarrhythmic mechanism for antiarrhythmic drugs or whether this action is specific for amiodarone. Therefore, we studied the affinity of one antiarrhythmic drug from every Vaughan-Williams group on T3 binding to human ThR beta(1) (hThR beta(1)). Second, we wished to investigate whether amiodarone is a competitive or noncompetitive inhibitor. hThR beta(1), expressed in insect cells using a recombinant baculovirus, was used in regular binding competition assays. Disopyramide, lignocaine, propafenone, metoprolol, dl-sotalol, and verapamil had no effect on T3 binding to hThR beta(1). Amiodarone showed a noncompetitive binding pattern at low concentrations (0.25-2 mu M) and a competitive binding at high concentrations (2-8 mu M). Among the antiarrhythmics tested, only amiodarone had affinity for hThR beta(1). This may represent a novel type of antiarrhythmic mechanism. The finding that amiodarone, in concentrations corresponding to therapeutic range in plasma, shifts from a noncompetitive to a competitive inhibitor, is of clinical interest in comparisons of low- and high-dose treatment.